Intracellular protein degradation is mediated selectively by the Ubiquitin-Proteasome System (UPS)
and autophagic-lysosomal system in mammalian cells. Many cellular and physiological processes, such as cell
division, cell differentiation, and cellular demise, are fine-tuned via the UPS-mediated protein degradation.
Notably, impairment of UPS contributes to human disorders, including cancer and neurodegeneration. The proteasome-
dependent N-degron pathways mediate the degradation of proteins through their destabilizing aminoterminal
residues. Recent advances unveiled that targeting N-degron proteolytic pathways can aid in sensitizing
some cancer cells to chemotherapeutic agents. Furthermore, interestingly, exploiting the N-degron feature, the
simplest degradation signal in mammals, and fusing it to a ligand specific for Estrogen-Related Receptor alpha
(ERRa) has demonstrated its utility in ERRa knockdown, via N-terminal dependent degradation, and also
its efficiency in the inhibition of growth of breast cancer cells. These recent advances uncover the therapeutic
implications of targeting and exploiting N-degron proteolytic pathways to curb growth and migration of
Keywords: Cancer cell death, apoptosis, N-degron, N-end rule, protein degradation, proteolysis, ubiquitin, proteasome, PROTACS.
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